Leiomyosarcoma is an aggressive type of soft tissue neoplasm that originates from smooth muscle cells; it is typically found in the uterus, gastrointestinal tract, and retroperitoneum. Primary leiomyosarcoma of bone is an extremely rare phenomenon first reported in 1965. Here, we present a case of primary leiomyosarcoma of bone occurred in the proximal humerus of a 41-year-old man who was referred to our orthopaedic clinic with a chief complaint of persistent left shoulder pain. Radiological investigations revealed a proximal lesion of the left humerus with periosteal reaction. Core needle biopsy of the lesion was performed later, which pointed to primary leiomyosarcoma of bone as the underlying pathology. Subsequently, complete resection of the lesion and prosthetic replacement of the proximal humorous were performed. The patient was followed three months after the surgery, and no sign of local recurrence or metastatic lesion was detected. To the best of our knowledge, this is the first case report of primary leiomyosarcoma of bone in Iran.